The invention relates to methods and products for treatment and/or prevention of platelet related thrombotic and other vaso-occlusive disorders.
Conditions resulting from thrombotic or thromboembolic events are the leading causes of illness and death in adults in western civilization. A great deal of effort and monetary resources have been directed towards understanding the mechanisms involved in vascular occlusive diseases involving thrombotic and thromboembolic events. These efforts have yielded a number of promising therapeutic agents. Notwithstanding the effort and financial resources that have been invested, these conditions still account for the vast majority of illness and death in the adult populations of developed nations.
Platelets are an important cellular component of blood involved in hemostasis as well as thrombotic or thromboembolic events. Abnormally high platelet counts such as those that result from hematological proliferative disorders such as for example essential thrombocythemia have been recognized as an important risk factor in thrombus formation. Furthermore, it has long been accepted that aspirin, which is known to inhibit cyclooxygenase and thereby prevents production of thromboxane A2 in platelets, lowers the incidence of thrombotic or thromboembolic events. For platelets, therapeutic regimens thus far reported have as their aim an inhibition of platelet function (e.g., inhibition of platelet adhesion, aggregation or factor release). An alternative modality is the reduction in platelet count in patients with abnormally high levels in certain hematological malignancies to levels approximating normal levels. Therapeutic intervention for reducing platelet count to low normal or below normal levels in subjects without myeloproliferative disorders has not been proposed primarily since normal platelet count has been thought to be critical to normal hemostasis.
The invention in a broad aspect involves the surprising discovery that subjects, including those with normal levels of circulating platelets, can unexpectedly derive medical benefit from a reduction in platelet count to below normal levels, without serious adverse consequences as a result of the platelet count reduction. The benefit may be proportional or correlative to the reduction in platelet count in a broad safety range. Thus in situations where it is desirable to inhibit a pathological condition or process mediated in part by normal levels of circulating platelets, subjects can be treated to lower platelet count preferably to a below normal level, thereby inhibiting the development, progression or propagation of the condition or accelerating or enhancing its regression. The methods of the invention are also useful for reducing the incidence of abnormal vessel growth induced by the presence of platelets.
A method is provided for treating a subject to reduce the risk of developing an adverse condition or to inhibit the progression and consequences of an adverse condition mediated at least in part by platelets. In some aspects, the subject is treated to reduce platelet count to low normal levels, while in other aspects the subject is treated to reduce platelet count to below normal levels. In one embodiment, the subject is treated with a pharmaceutical agent.
In one aspect, the invention provides a method for treating a subject to inhibit a vaso-occlusive event. Inhibiting a vaso-occlusive event means to prevent the formation of a vaso-occlusive event, to reduce progression and consequences of an already established vaso-occlusive event or to induce regression of a vaso-occlusive event. The invention also provides other methods aimed at reducing morbidity or mortality of subjects from vasoocclusive events such as but not limited to thrombotic events which may lead to total or partial vessel blockage by thrombus, or arterial stenosis due to excessive cell proliferation.
The methods of the invention comprise administering to a subject in need of such treatment an agent that reduces platelet count in the subject. The agent is administered in an amount effective to reduce platelet count in the subject to at least a low normal level. Such reductions in platelet count will reduce morbidity and/or mortality and thereby provide patient outcome benefit.
As used herein, a vaso-occlusive event includes a pathological partial occlusion (including a narrowing) or complete occlusion of a blood vessel, a stent or a vascular graft. A vaso-occlusive event intends to embrace thrombotic or thromboembolic events, and the vascular occlusion disorders or conditions to which they give rise. Thus, a vaso-occlusive event is intended to embrace all vascular occlusive disorders resulting in partial or total vessel occlusion from thrombotic or thromboembolic events, except those that are related to high platelet count due to a hematological proliferative disorder. A thrombotic event as used herein is meant to embrace both a local thrombotic event and a distal thrombotic event (e.g., a thromboembolic event such as for example an embolic stroke). A vaso-occlusive event also includes abnormal blood vessel growth induced by the presence of platelets and the factors they secrete. An example of this latter form of vaso-occlusive event is intimal hyperplasia which results in a narrowing of the blood vessels (i.e., reduction in the diameter of blood vessels either locally or throughout an extended segment of the vessel) due to a hyperproliferation of cells of the intimal layer of the blood vessel wall.
Preferably, the subject is otherwise free of symptoms calling for treatment with the agent. In some embodiments, the subject is preferably free of symptoms associated with a hematological proliferative disorder such as for example myeloproliferative disease. Preferably, the subject is a human subject, but is not so limited. In another embodiment, the subject is apparently healthy. In preferred embodiments, the subjects do not have abnormally elevated platelet levels (i.e., a platelet count that is higher than the normal range) that are caused by a hematological proliferative disorder. Thus preferably, the subjects do not have a hematological proliferative disorder. In an important embodiment, the subject has a normal platelet count prior to treatment. In some embodiments, the subject has a higher platelet count than the mean normal level but is still considered within the normal range. As an example, a subject with a platelet count of 450xc3x97103 platelets per xcexcl is considered to be at the high end of the normal range and is intended to be treated by the methods of the invention. In some embodiments, the subject may have a platelet count above the usual range, but without any underlying hematological proliferative disorder. In another embodiment, the subject is not a post-menopausal female.
In some aspects, the invention intends to treat subjects who are at risk of a vaso-occlusive event. These subjects may or may not have had a previous vaso-occlusive event. The invention embraces the treatment of subjects prior to a vaso-occlusive event, at a time of a vaso-occlusive event and following a vaso-occlusive event. Thus, as used herein, the xe2x80x9ctreatmentxe2x80x9d of a subject is intended to embrace both prophylactic and therapeutic treatment, and can be used both to limit or to eliminate altogether the symptoms or the occurrence of a vaso-occlusive event. In one embodiment, the subject may exhibit symptoms of a vaso-occlusive event.
The invention also intends to embrace the treatment of a subject that has an abnormally elevated risk of a vaso-occlusive event such as a thrombotic event. The subject may have vascular disease. The vascular disease may be selected from the group consisting of arteriosclerosis, cardiovascular disease, cerebrovascular disease, renovascular disease, mesenteric vascular disease, pulmonary vascular disease, ocular vascular disease or peripheral vascular disease.
In another embodiment, the subject has had a primary vaso-occlusive event such as a primary thrombotic event. The agent may be administered to a subject following a primary vaso-occlusive event. The method of the invention embraces treatment of a subject to reduce the risk of a secondary thrombotic event or to inhibit the propagation of an existing thrombotic event. The thrombotic event may be selected from the group consisting of arterial thrombosis, coronary thrombosis, heart valve thrombosis, coronary stenosis, stent thrombosis and graft thrombosis. The vaso-occlusive event also includes disorders or conditions that may arise from a thrombotic event or a thromboembolic event and in this regard a vaso-occlusive event includes but is not limited to myocardial infarction, stroke and transient ischemic attack. In an important embodiment the vaso-occlusive event is myocardial infarction. In one embodiment, the subject has had a myocardial infarction. A subject who has hypercholesterolemia, hypertension or atherosclerosis also can be treated by the methods of the invention.
In yet another embodiment, the subject is one who will undergo an elective surgical procedure. The agent may be administered to such a subject prior to the elective surgical procedure. The method of the invention can also be directed towards a subject who has undergone a surgical procedure. As used herein, a surgical procedure is meant to embrace those procedures that have been classically regarded as surgical procedures as well as interventional cardiology procedures such as arteriography, angiography, angioplasty and stenting. Thus, the surgical procedure, whether elective or not, can be selected from the group consisting of coronary angiography, coronary stent placement, coronary by-pass surgery, carotid artery procedure, peripheral stent placement, vascular grafting, thrombectomy, peripheral vascular surgery, vascular surgery, organ transplant, artificial heart transplant, vascular angioplasty, vascular laser therapy, vascular replacement, prosthetic valve replacement and vascular stenting.
In a preferred embodiment, the agent is anagrelide. In one embodiment, the agent is a derivative of anagrelide. In important embodiments, the agent is not a 2-aryl benzo[b]thiophene. In other important embodiments, the agent is not raloxifene hydrochloride. However, the agent is not an MPL pathway inhibitory agent (i.e., the agent does not impact upon the signal transduction pathway involving thrombopoietin and the Mpl receptor).
The agent is administered in an amount effective to reduce platelet count, in the subject, preferably to at least low normal levels. In one embodiment, the agent is administered in an amount ranging from 30 xcexcg/kg/day to 150 xcexcg/kg/day. In another embodiment, the agent is administered in an amount ranging from 1 xcexcg/kg/day to 150 xcexcg/kg/day. In some embodiments, these latter ranges are preferred when the agent is anagrelide or an anagrelide derivative.
In one embodiment, the agent is administered in an amount effective to reduce the platelet count to at least low normal levels if the subject has a normal platelet count prior to treatment.
In some embodiments, the agent is administered in an amount effective to reduce the platelet count to below normal levels if the subject has an above normal platelet count prior to treatment. In these latter embodiments, the subject may not have a hematological proliferative disorder, but is not so limited.
Depending upon the particular embodiment, the platelet count is reduced anywhere from at least 10% to 95% of pre-treatment levels. In particular embodiments, the platelet count is reduced by at least 90%, at least 80%, at least. 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, or at least 10%. In some important embodiments, the platelet count is reduced by more than 10%. In another embodiment, platelet count is reduced by more than 30% or by more than 40%.
In some embodiments that embrace the treatment of a human subject, platelet count is preferably reduced to below 200xc3x97103 platelets per pt, and in still others to below 150xc3x97103 platelets per xcexcl. In still another embodiment, platelet count is reduced to below 100xc3x97103 platelets per xcexcl of blood in a human subject. In embodiments in which the platelet count is reduced to a low normal level this is defined as 10% less than the mean normal platelet count. In other embodiments, the platelet count is reduced to below normal levels.
In yet another embodiment, the agent is administered in an amount effective to reduce the platelet count by at least 10% and to an amount above 200xc3x97103 platelets per xcexcl. In other embodiments, the agent is administered in an amount effective to reduce the platelet count by at least 10% and below 200xc3x97103 platelets per xcexcl. In other embodiments, the agent is administered in an amount effective to reduce the platelet count by at least 20% and to below 200xc3x97103 platelets per xcexcl.
The agent of the invention can be administered simultaneously or consecutively with another therapeutic compound such as an agent which would normally be indicated for the subject. Such agents include agents for treating vascular disease or vascular complications (i.e., complications resulting from such disease). In some important embodiments, the agent for treating vascular disease or vascular complications is an anti-thrombotic agent. The anti-thrombotic agent may be selected from the group consisting of an anti-coagulant agent, a fibrinolytic agent and an inhibitor of platelet function, but is not so limited. Thus, in one embodiment, the agent is administered with an inhibitor of platelet function. The inhibitor of platelet function may be selected from the group consisting of aspirin, abciximab, clopidogrel and dipyridamole. In another embodiment, the agent may be administered with an anti-coagulant agent. The anti-coagulant may be selected from the group consisting of glycosaminoglycans (e.g., heparins) and vitamin K antagonists. In a further embodiment, the agent is administered with a fibrinolytic agent, such as but not limited to one selected from the group consisting of plasminogen activators such as tissue plasminogen activator (TPA), streptokinase and urokinase, plasmin and plasminogen. Depending upon the embodiment, the agent of the invention may be administered before, simultaneously with or following administration of the agent for treating vascular disease or vascular complications.
Other useful categories of such agents include but are not limited to anti-inflammatory agents, anti-platelet agents, lipid reducing agents, direct thrombin inhibitors, glycoprotein IIb/IIIa receptor inhibitors, agents that bind to cellular adhesion molecules and inhibit the ability of white blood cells to attach to such molecules, calcium channel blockers, beta-adrenergic receptor blockers, cyclooxygenase-2 inhibitors, and angiotensin system inhibitors.
In one embodiment, the agent is administered following a primary vaso-occlusive event such as a thrombotic event. The agent can be administered in a number of ways, including enteral and parenteral routes. In some preferred embodiments, the agent is administered in a sustained release device.
The invention also provides a number of pharmaceutical preparations comprising agents that reduce platelet count. The pharmaceutical preparations of the invention comprise one or more agents that reduce platelet count and a pharmaceutically acceptable carrier. The agent is present in the pharmaceutical preparation in an amount effective to reduce platelet count. In important embodiments of the invention, the pharmaceutical preparation comprises the agent in an amount effective to reduce platelet count to low normal levels or to below normal levels.
In yet a further aspect, the invention provides a sustained release device that comprises an agent that reduces platelet count in a subject, wherein the agent is released for at least 7 days. In one embodiment, the sustained release device further comprises an agent for treating vascular disease or vascular complications. The an agent for treating vascular disease or vascular complications may be an anti-thrombotic agent but is not so limited. In one embodiment, the anti-thrombotic is selected from the group consisting of an anti-coagulant agent, a fibrinolytic agent and an inhibitor of platelet function.
Preferably, the agent is released from the sustained release device in an amount effective to reduce platelet count in a subject to low normal or below normal levels. In one embodiment the agent is anagrelide or a derivative of anagrelide. Depending upon the embodiment and the nature of the agent, the sustained release device may release the agent at a rate ranging from 30 xcexcg/kg/day to 150 xcexcg/kg/day. In other embodiments, the agent may be released at a rate ranging from 1 xcexcg/kg/day to 150 xcexcg/kg/day. In one embodiment, the sustained release device releases the agent for at least 30 days. In other embodiments, the agent is released for at least 6 months, for at least 1 year, for at least 2 years or for at least 5 years or more. Preferably, the agent is released in an effective amount that does not affect platelet function.
In another aspect, a subject""s blood is treated extracorporeally to reduce platelet count to low normal or below normal levels, using procedures such as by pheresis or adsorption of platelets and removal. Subjects, target platelet count and concurrent therapies are as described above. This aspect of the invention is particularly suited to acute therapy, although it is not so limited.